rs727502819
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong
The NM_172362.3(KCNH1):c.1480A>G(p.Ile494Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I494T) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
KCNH1
NM_172362.3 missense
NM_172362.3 missense
Scores
8
5
4
Clinical Significance
Conservation
PhyloP100: 6.01
Genes affected
KCNH1 (HGNC:6250): (potassium voltage-gated channel subfamily H member 1) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_172362.3
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr1-210804148-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1690786.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
Missense variant where missense usually causes diseases, KCNH1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.816
PP5
?
Variant 1-210804149-T-C is Pathogenic according to our data. Variant chr1-210804149-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 162520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-210804149-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH1 | NM_172362.3 | c.1480A>G | p.Ile494Val | missense_variant | 8/11 | ENST00000271751.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH1 | ENST00000271751.10 | c.1480A>G | p.Ile494Val | missense_variant | 8/11 | 2 | NM_172362.3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Zimmermann-Laband syndrome 1 Pathogenic:2
Pathogenic, no assertion criteria provided | not provided | Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2015 | - - |
Temple-Baraitser syndrome;C4551773:Zimmermann-Laband syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Aug 04, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 20, 2021 | - - |
Temple-Baraitser syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;.;.
REVEL
Pathogenic
Sift
Benign
T;.;T;.;.
Sift4G
Benign
T;.;T;.;.
Polyphen
0.99
.;.;D;.;.
Vest4
MutPred
0.66
.;Loss of catalytic residue at T499 (P = 0.3697);Loss of catalytic residue at T499 (P = 0.3697);.;.;
MVP
MPC
2.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at